Severe acne can have profound psychological and physical morbidity for millions of affected patients. The goal of this proposal is to determine how isotretinoin, a potent drug for acne exerts its effects in the sebacous gland. Isotretinoin (13-c/s retinoic acid) is an oral retinoid that is the only agent effective against severe acne that targets each of the pathogenic factors of this disease. 13-c/s RA and other oral retinoids are also used in cancer chemotherapy. Isotretinoin however is a known teratogen whose use is now restricted within an FDA-mandated registry system. Lack of understanding of the mechanism of action of 13-cis RA in the sebaceous gland has hampered the progress to find safe alternatives. Our preliminary data indicate that 13-cis RA induces apoptosis and cell cycle arrest in sebocytes. Gene array expression analysis in sebocytes and in human skin indicates that 13-cis RA induces genes involved in the innate immune response, including lipocalin 2 that encodes a multifunctional secretory protein, neutrophil gelatinase associated lipocalin (NGAL) involved in renal epithelial morphogenesis, defense against bacterial pathogens and in apoptosis. The major goal of this project is to test the hypothesis that 13- cis RA acts by a metabolite or metabolites to activate a pattern of transcriptional activation leading to the expression of apoptotic mediators, such as NGAL, that act specifically on sebaceous glands. Aim 1 will use our sebocyte model system to test the widely held hypothesis that 13- c/s RA, as a reservoir of potent retinoids, is superior to its individual metabolites in inducing apoptosis. Subaims are directed determining how 13-cis RA differs from all-trans RA and whether the apoptotic effects induced by 13-cis RA are mediated by retinoid receptors. Aim 2 will test the hypothesis that NGAL is an important mediator of apoptosis and Aim 3 will test the hypothesis that the sebocyte-selective apoptotic response to 13- cis RA and NGAL is due to differential expression of NGAL receptor isoforms. The findings of these studies not only have the potential to advance our understanding of retinoid action in acne, but can lead to advances in the understanding of these agents in cancer biology and in innate immunity as well. [unreadable] [unreadable] [unreadable]